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Abstract
Grant Number: 5R43AI052630-02 PI Name: WELLS, JAMES A. PI Email: jaw@sunesis.com PI Title: Project Title: HIV Integrase Drug Discovery Using Tethering Technology Abstract: DESCRIPTION (provided by applicant): The long-term objective of this proposal is to apply a powerful new "covalent tethering" technology to the discovery of novel therapeutics that inhibit HIV integrase for the treatment of AIDS. Although drugs that block HIV integrase activity would strongly complement the existing arsenal of anti-HIV therapeutics, the discovery of lead compounds using traditional methods has thus far been largely unsuccessful. Covalent tethering technology involves the discovery of drug-like "fragments" that bind to a protein target, followed by their assembly by chemical linkage into potent inhibitors. This "screen-then-link" process is much more efficient and offers a greater survey of chemical diversity space than the typical lead discovery paradigm, in which large compound libraries are first created and then screened in a functional assay. Covalent tethering relies on the selective capture of sulfhydryl-containing fragment molecules on cysteine residues introduced on the surface of a target protein. We propose to conduct a full survey of the HIV integrase active site surface by screening a series of cysteine mutants versus our custom library of >I 0,000 sulfhydryl-containing inhibitor fragments. For promising fragments, disulfide tethers will be removed and appropriate combinations will be fused using structure-base design, to generate compounds that bind non-covalently and serve as starting points for medicinal chemistry.
Thesaurus Terms:
active site, antiAIDS agent, covalent bond, drug discovery /isolation, enzyme inhibitor, integrase, protein binding, virus protein
antiviral agent, chemical binding, cysteine
X ray crystallography, mass spectrometry
Institution: SUNESIS PHARMACEUTICALS, INC. 341 OYSTER POINT BLVD SOUTH SAN FRANCISCO, CA 94080 Fiscal Year: 2003 Department: Project Start: 01-JUL-2002 Project End: 30-JUN-2004 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZRG1